Is it Time to Re-Evaluate Our Experimental Approach to Studying Diffuse Podocytopathies?
Authors: Andrew J.B. Watts, Astrid Weins
Journal: Journal of the American Society of Nephrology (2022)

Minimal change disease (MCD) and primary FSGS are diffuse podocytopathies of unclear etiology that affect both adults and children.1 For decades, immune dysfunction involving a circulating permeability factor1 has been postulated as the underlying cause. There is now strong, emerging evidence that B cells2 and autoantibodies may be central to the pathogenesis of MCD. Underscoring this notion, recent studies identified circulating autoantibodies directed against podocyte antigens in patients with MCD,34–5 together with a unique pattern of IgG deposition in the kidney.3 A direct pathogenic role of antibodies against podocyte antigens is further supported by massive proteinuria and histologic features of MCD when the antibodies are administered to mice.56–7 However, to date, no similar murine model of autoimmune-associated massive proteinuria by active immunization with a podocyte antigen exists. In their study, Hada et al.8 developed a novel mouse model of massive proteinuria by active immunization with the recombinant extracellular domain of murine crumbs cell polarity complex component 2 (Crb2), which is ubiquitously expressed in epithelial-derived tissues, where it localizes to the foot processes of podocytes and interacts with nephrin.9 Active immunization with either a single injection or three injections resulted in significant and sustained albuminuria beginning around week 5, which was associated with autoantibodies against Crb2 in both the serum and the kidney, with histologic features reminiscent of human MCD. A subset of mice receiving three injections also developed hematuria, a higher level of proteinuria, and histologic features of FSGS. Specific autoantibodies directed against Crb2 have not been identified in patients with MCD or FSGS. Although relevance to human disease is yet to be determined, the importance of Crb2 in the slit diaphragm and in glomerular barrier function has been demonstrated, as it has for nephrin, through podocyte-specific knockout mouse models9 and in patients with steroid-resistant nephrotic syndrome harboring mutations.10 Therefore, even in the absence of specific and direct relevance of Crb2 autoantibodies to human podocytopathies, this unique and powerful mouse model system could be useful for not only gaining insight into the immunologic landscapes in different disease stages that may underlie the responses to various immunotherapies, but also in exploring the specific role of Crb2 in regulating correct trafficking of slit diaphragm components in podocyte health and disease. Recent evidence pointing to direct pathogenic involvement of specific autoantibodies in a subset of diffuse podocytopathies reveals a new opportunity for the scientific community to critically re-evaluate experimental models for suitability and relevance. The findings reported using this novel murine model raise the intriguing question of whether the immunogenic effects described here are unique to Crb2 or whether other podocyte antigens could be used to generate similar models of disease. Understanding all pathophysiologic processes involved in autoimmune podocytopathies is essential for tailoring available and advancing novel targeted immunologic and nonimmunologic therapies. This model can serve as one important strategic tool in this massive and critical effort. Disclosures A. Weins reports having consultancy agreements with Goldfinch Bio, Pfizer, and Sail Bio; receiving honoraria from Sysmex. A. Weins and A.J.B. Watts report having a patent filed for methods for diagnosing and treating autoimmune podocytopathies. Funding None.